AMPK inhibitor Compound C stimulates ceramide production and promotes Bax redistribution and apoptosis in MCF7 breast carcinoma cells

被引：102

作者：

Jin, Junfei ^{[1
,2
]}

Mullen, Thomas D. ^{[3
]}

Hou, Qi ^{[1
,4
]}

Bielawski, Jacek ^{[1
]}

Bielawska, Alicja ^{[1
]}

Zhang, Xiaoming ^{[1
]}

Obeid, Lina M. ^{[3
,5
]}

Hannun, Yusuf A. ^{[1
]}

Hsu, Yi-Te ^{[1
]}

机构：

[1] Med Univ S Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA

[2] Univ S China, Res Ctr Life Sci, Hengyang 421001, Hunan, Peoples R China

[3] Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA

[4] Peking Union Med Coll, Inst Mat Med, Dept Pharmacol, Beijing 100050, Peoples R China

[5] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC 29401 USA

来源：

JOURNAL OF LIPID RESEARCH | 2009年 / 50卷 / 12期

基金：

美国国家卫生研究院;

关键词：

AMP-activated protein kinase signaling pathway; sphingolipid; cell death; ACTIVATED PROTEIN-KINASE; MITOCHONDRIAL-MEMBRANE; ACID SPHINGOMYELINASE; DEPENDENT PATHWAY; SALVAGE PATHWAY; SYNTHASE; FAMILY; PROLIFERATION; SPHINGOLIPIDS; TRANSLOCATION;

D O I：

10.1194/jlr.M900119-JLR200

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

Compound C is commonly used as an inhibitor of AMP-activated protein kinase (AMPK), which serves as a key energy sensor in cells. In this study, we found that Compound C treatment of MCF7 cells led to Bax redistribution from the cytoplasm to mitochondria and cell death. However, this effect does not involve AMPK. In addition, we found that treatment with this compound leads to an enhanced ceramide production. Analyses by quantitative PCR and ceramide synthase activity assay suggest that ceramide synthase 5 (LASS/CerS 5) is involved in Compound C-induced ceramide upregulation. Downregulation of LASS/CerS 5 was found to attenuate Compound C-mediated ceramide production, Bax redistribution, and cell death.-Jin, J., T. D. Mullen, Q. Hou, J. Bielawski, A. Bielawska, X. Zhang, L. M. Obeid, Y. A. Hannun, and Y-T. Hsu. AMPK inhibitor Compound C stimulates ceramide production and promotes Bax redistribution and apoptosis in MCF7 breast carcinoma cells. J. Lipid Res. 2009. 50: 2389-2397.

引用

页码：2389 / 2397

页数：9

共 45 条

[1]

The Bcl-2 protein family: Arbiters of cell survival [J].

Adams, JM ;

Cory, S .

SCIENCE, 1998, 281 (5381) :1322-1326

[2]

Metformin prevents an adaptive increase in GSH and induces apoptosis under the conditions of GSH deficiency in H4IIE cells [J].

Bae, Eun Ju ;

Cho, Min Joo ;

Kim, Sang Geon .

JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH-PART A-CURRENT ISSUES, 2007, 70 (15-16) :1371-1380

[3]

Simultaneous quantitative analysis of bioactive sphingolipids by high-performance liquid chromatography-tandem mass spectrometry [J].

Bielawski, Jacek ;

Szulc, Zdzislaw M. ;

Hannun, Yusuf A. ;

Bielawska, Alicja .

METHODS, 2006, 39 (02) :82-91

[4]

A mitochondrial pool of sphingomyelin is involved in TNFα-induced Bax translocation to mitochondria [J].

Birbes, H ;

Luberto, C ;

Hsu, YT ;

Bawab, SEL ;

Hannun, YA ;

Obeid, LM .

BIOCHEMICAL JOURNAL, 2005, 386 :445-451

[5]

Mutations in the γ2 subunit of AMP-activated protein kinase cause familial hypertrophic cardiomyopathy:: evidence for the central role of energy compromise in disease pathogenesis [J].

Blair, E ;

Redwood, C ;

Ashrafian, H ;

Oliveira, M ;

Broxholme, J ;

Kerr, B ;

Salmon, A ;

Östman-Smith, I ;

Watkins, H .

HUMAN MOLECULAR GENETICS, 2001, 10 (11) :1215-1220

[6]

Bax translocates to mitochondria of heart cells during simulated ischaemia: involvement of AMP-activated and p38 mitogen-activated protein kinases [J].

Capano, M ;

Crompton, M .

BIOCHEMICAL JOURNAL, 2006, 395 :57-64

[7]

Long-term Forskolin Stimulation Induces AMPK Activation and Thereby Enhances Tight junction Formation in Human Placental Trophoblast BeWo Cells [J].

Egawa, M. ;

Kamata, H. ;

Kushiyama, A. ;

Sakoda, H. ;

Fujishiro, M. ;

Horike, N. ;

Yoneda, M. ;

Nakatsu, Y. ;

Ying, Guo ;

Jun, Zhang ;

Tsuchiya, Y. ;

Takata, K. ;

Kurihara, H. ;

Asano, T. .

PLACENTA, 2008, 29 (12) :1003-1008

[8]

Compound C inhibits hypoxic activation of HIF-1 independent of AMPK [J].

Emerling, Brooke M. ;

Viollet, Benoit ;

Tormos, Kathryn V. ;

Chandel, Navdeep S. .

FEBS LETTERS, 2007, 581 (29) :5727-5731

[9]

Bid induces the oligomerization and insertion of Bax into the outer mitochondrial membrane [J].

Eskes, R ;

Desagher, S ;

Antonsson, B ;

Martinou, JC .

MOLECULAR AND CELLULAR BIOLOGY, 2000, 20 (03) :929-935

[10]

Bax-induced caspase activation and apoptosis via cytochrome c release from mitochondria is inhibitable by Bcl-xL [J].

Finucane, DM ;

Bossy-Wetzel, E ;

Waterhouse, NJ ;

Cotter, TG ;

Green, DR .

JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (04) :2225-2233

← 1 2 3 4 5 →